Synthesis of (R) and (S)-aminocarnitine, (R) and (S)-4-phosphonium-3-amino-butanoate, (R) and (S) 3,4-diaminobutanoic acid, and their derivatives starting from D- and L-aspartic acid

ABSTRACT

A process is described for the preparation of R or S aminocarnitine, R or S phosphonium aminocarnitine and R and S 3,4 diaminobutanoic acid, and their derivatives with the following formula:  
                 
 
     where Y is as described in the attached description, starting from aspartic acid with the same configuration as the desired compounds. This process is advantageous from the industrial point of view in terms of the type of reactants used, the reduced volumes of solvents and the possibility of avoiding purification of the intermediate products.

[0001] This application is a continuation-in-part of application Ser.No. 10/338,045 filed Jan. 8, 2003, which is a continuation-in-part ofSer. No. 10/018,794 filed Dec. 21, 2001, now U.S. ______ which is a 35USC §371 of PCT/IT00/00258 filed Jun. 23, 2000.

[0002] The invention described herein relates to a process for theproduction of (R) and (S)-aminocarnitine and its derivatives startingfrom D- and L-aspartic acid. The same process can be applied to produceother related compounds such as (R) and(S)-4-phosponium-3-amino-butanoate and its derivatives or (R) and (S)3,4-diamino butanoic acid dihydrochloride.

[0003] Aminocarnitine is a substance endowed with interestingpharmaceutical properties and its N-derivatives arouse a similar degreeof interest. For example, D. L. Jenkins and W. O. Griffith havedescribed the antiketogenic and hypoglycaemic effects of theN-acetylates in the racemic form. U.S. Pat. No. 4,521,432 (Takeda)describes the possible applications of (−)-N-acetyl-aminocamitine, innersalt, in the treatment of the complications of diabetes. Similaractivity has been described for (+)-aminocarnitine, chloridehydrochloride. It would therefore be of interest to have processes forthe preparations of the enantiomorph, which match up to the criteria ofeconomic convenience on an industrial scale.

[0004] R(+)-aminocarnitine is obtained via hydrolysis ofR-(−)-N-acetylcarnitine, the latter being isolated by the cultivation ofmicro-organisms of the genera Emericella or Aspergillus, or,alternatively, via a complex chemical process described in the Takedapatent cited above.

[0005] Other methods of chemical synthesis are known, all rathercomplex, such as, for example, the one described by Shinagawa, J. Med.Chem., 30; 1458 (1987), who uses diazomethane, which is known to behazardous. In any event, this method is not of industrial interest, inthat it was conceived in order to ascertain the absolute configurationof the single enantiomorph.

[0006] The single enantiomorphs can also be obtained by resolution ofthe racemic mixture of (±)-N-acetylaminocarnitine, as described in EP 0287 523.

[0007] Alternatively, R(+)- and S(−)-aminocarnitine chloride can beobtained by resolution on silica gel chromatography or fractionalcrystallisation of the respective N-α-methylbenzyl, benzylesterchlorides, as described in Italian patent 1,231,751. This process, whichinvolves subsequent debenzylation is laborious and not very suitable forindustrial-scale production.

[0008] A method is also known using chiral carnitine as a startingproduct (Journal of Organic Chemistry, 1995, 60, 8318-8319; (Sigma-Tau)EP 636603, 1995). This method uses reagents such as methane-sulphonicanhydride and sodium azide and solvents such as anhydrousdimethylsulphoxide, and involves a catalytic reduction step.

[0009] A process has now been found for the preparation of singleenantiomorphs starting from D-aspartic acid and L-aspartic acid,respectively, with an overall yield of at least 38% in 6 to 7 steps, butwithout it being necessary to purify the intermediates. In pratice, theprocess according to the invention described herein is realised viadirect hydrolysis of the chiral aminocarnitine ester in an acidic milieuto yield a chiral aminocarnitine inner salt without purifying theintermediate products. The enantiomeric purity of the aminocarnitinethus obtained is >99%.

[0010] The same synthetic process can be performed to prepare newcompounds such as (R) and (S) 4-phosphonium-3-aminobutanoate(hereinafter referred as phosphonium aminocarnitine) and a chiralsynthon as (R) and (S) 3,4-diaminobutanoic acid dihydrochloride.

[0011] 4-phosphonium-3-aminobutanoate is potentially useful as CPTinhibitor with antiketogenic and hypoglycemic effects and as intemediatefor the synthesis of pharmacologically active compounds.

[0012] Thus, an object of the invention described herein is a processfor the preparation of (R) and (S)-aminocarnitine, (R) and (S)phosphonium aminocarnitine and of a number of their N-substitutedderivatives, and a process for the preparation of (R) and (S)3,4-diaminobutanoic acid dihydrochloride (Synlett 1990, 543-544; Synth.Comm. 1992, 22(6), 883-891). In particular, the invention describedherein provides a process which also enables aminocarnitine, phosphoniumaminocarnitine and 3,4-diaminobutanoic acid derivatives to be obtainedwhich are useful for the preparation of medicaments for the treatment ofdiseases associated with hyperactivity of carnitinepalmitoyltransferase.

[0013] These derivatives are described in Italian patent applicationMI98A001075, filed on May 15, 1998, and in international patentapplication PCT/IT99/00126, filed on May 11, 1999, both of which in thename of the applicant and incorporated herein for reference purposes.

[0014] The process according to the invention described herein allowsthe preparation of compounds with the following formula:

[0015] in which

[0016] W is Q(CH₃)₃ where Q is N or P or

[0017] W is NH₃

[0018] Y is hydrogen or one of the following groups:

[0019] —R₁,

[0020] —COR₁,

[0021] —CSR₁,

[0022] —COOR₁,

[0023] —CSOR₁,

[0024] —CONHR₁,

[0025] —CSNHR₁,

[0026] —SOR₁,

[0027] —SO₂R₁,

[0028] —SONHR₁,

[0029] —SO₂NHR₁,

[0030] where

[0031] R₁ is a straight or branched, saturated or unsaturated alkylcontaining from 1 to 20 carbon atoms, optionally substituted with an A₁group, where A₁ is selected from the group consisting of halogen, C₆-C₁₄aryl or heteroaryl, aryloxy or heteroaryloxy, which can optionally besubstituted with straight or branched, saturated or unsaturated loweralkyl or alkoxy, containing from 1 to 20 carbon atoms, halogens;

[0032] said process comprises the following steps:

[0033] a) conversion of D-aspartic or L-aspartic acid to N—Y substitutedD-aspartic or L-aspartic acid;

[0034] b) conversion of the N—Y substituted D-aspartic or L-asparticacid to the respective anhydride;

[0035] c) reduction of the anhydride obtained in step b) to thecorresponding 3-(NH—Y)-lactone;

[0036] d) opening of the lactone obtained in step c) to yield thecorresponding D- or L-3-(NH—Y)-amino-4-hydroxybutyric acid;

[0037] e) transformation of the 4-hydroxy group of the D- orL-3-(NH—Y)-amino-4-hydroxybutyric acid into a leaving group;

[0038] f) substitution of the end group in position 4 of the D- orL-3-(NH—Y)-aminobutyric acid with a trimethylammonium group or with atrimethylphosphonium group

[0039] g) hydrolysis of the ester group; and, if so desired,

[0040] h) restoration of the amino group.

[0041] The usefulness of this new synthesis route for optically pureaminocarnitine, as compared to the method involving the use of chiralcarnitine as the starting product (Journal of Organic Chemistry, 1995,60, 8318-8319; EP 0 636 603 (Sigma-Tau)), consists in the fact that theuse of reactants such as methane-sulphonic anhydride and sodium azide,of dimethyl-sulphoxide as a solvent, and of a catalytic reduction stepis avoided. What is more, the volumes involved are lower, thus allowingbetter management of the reactions and of any purification ofintermediate products. In fact, the process according to the inventionpresents the additional advantage that all steps can be carried outavoiding purification of the intermediates, without this jeopardisingthe purity of the end product. This advantageous characteristic isobvious to the expert in the art; in particular, the fact will beappreciated that that no purification operations are necessary whichwould place an additional burden on the synthesis process in terms ofeconomic costs, time, materials, specialised personnel and equipment.

[0042] As compared to the process described in Journal of MedicinalChemistry, 1987, 30, 1458-1463 (Takeda), involving the use ofbenzyloxycarbonyl-L-asparagine as the starting product (with 7 steps anda 24% overall yield), the advantage at industrial level of avoidingreactants such as diazomethane, silver benzoate and dimethyl-sulphateappears obvious. In another process (Bioorganic & Medicinal ChemistryLetters, 1992, 2 (9), 1029-1032), (R)-aminocarnitine is obtainedstarting from a derivative of aspartic acid (the tert-butylester ofN-benzyloxycarbonyl-L-aspartic acid) in seven steps with a yield of 24%22%, but again using reactants such as diazomethane and silver benzoate,a catalytic hydrogenation step, and methylation with methyl iodide.

[0043] In these previously mentioned syntheses, the only product thatcan be obtained is (R)-aminocarnitine. The great versatility of this newroute allows instead to obtain several compounds such as (R)-phosphoniumaminocarnitine and (R) 3,4-diaminobutanoic acid dihydrochloride, justchanging the incoming nucleophile.

[0044] The processes which are the subject of the invention describedherein are described in the scheme, for (R)-forms. It is absolutelyobvious to the expert in the sector that the case of S-(−)-forms isequally described by the scheme and that no modification is necessary,apart from the fact that the starting compound is of the oppositeconfiguration, namely S-(−)-aspartic acid.

[0045] In the context of the invention described herein, examples of thestraight or branched C₁-C₂₀ alkyl group are methyl, ethyl, propyl,butyl, pentyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl andeicosyl and their possible isomers, such as, for example, isopropyl,isobutyl and tert-butyl.

[0046] Examples of the (C₆-C₁₄) aryl, or (C₆-C₁₄) aryloxy, heteroaryl orheteroaryloxy group, possibly substituted with straight of branchedalkyl or alkoxy with from 1 to 20 carbon atoms, said alkyl group beingas exemplified above, are phenyl, 1- or 2-naphthyl, anthracenyl, benzyl,2-phenylethyl 1-phenylethyl, 3-phenylpropyl, 2-anthracenylpropyl,1-anthracenylpropyl, naphthylmethyl, 2-naphthylethyl, 1-naphthylethyl,3-naphthylpropyl, 2-naphthyl-propyl, 1-naphthylpropyl, cyclohexylmethyl,5-phenylpentyl, 3-phenylpentyl, 2-phenyl-3-methylbutyl, thienyl,quinolyl, pyridyl, 5-tetrazolyl, and the equivalent ether derivatives.

[0047] What is meant by halogen is fluorine, chlorine, bromine, oriodine.

[0048] In a first embodiment of the invention described herein, theprocess involves steps a)-g), and optionally h), described above.According to this first realisation, and with reference to the schemegiven above, commercial chiral aspartic acid 1 is treated with areactant suitable for introducing the Y group on the nitrogen atom. Thisstep both functions to protect the amino group in the subsequent stepsof the process and, if suitably selected, represents the group whichwill be present in the end compound, according to the meaningsattributed above to the Y group.

[0049] Assuming that, in the end compound, the Y group is other thanhydrogen, different cases may be envisaged in the process according tothe invention.

[0050] In the case in which Y is R₁, the substitution reaction of ahydrogen of the amino group takes place by reaction withalkancarbaldehydes, where the alkyl portion is a homologue of an lowerterm of the R₁ group desired, and subsequent reduction.

[0051] When Y is —COR₁, —CSR₁, —COOR₁, —CSOR₁, —CONHR₁, —CSNHR₁, —SOR₁,—SO₂R₁, —SONHR₁ and —SO₂NHR₁, the compounds are obtained by reactionwith acylic chlorides, thioacylic chlorides, alkyl chloroformates, alkylthiochloroformates, alkyl isocyanates, alkyl thioisocyanates, alklysulphinyl chlorides, alkyl sulphonyl chlorides, SOCl₂ and alkyl amines,alkyl sulphamoyl chlorides (or SO₂Cl₂ and alkyl amines), containing thedesired alkyl R₁ group.

[0052] As regards the different meanings of R₁, present in the variousreactants, these are available commercially, or can be preparedaccording to known methods described in the literature, to which theexpert in the art may refer, completing his general knowledge of thesubject.

[0053] In a second embodiment of the invention described herein, theprocess involves steps a)-c), and then a step c′), that is to say theopening of the lactone with the introduction of a leaving group X,followed by step 1) or by steps f) and g) and optionally h), describedabove.

[0054] In a third embodiment of the invention described herein, theprocess requires that step f), which has been reached according to oneof the first two embodiments of the invention, be followed by step i),i.e. the direct transformation of the ester of the N—Y substitutedaminocarnitines to aminocarnitines. In a fourth embodiment of theinvention described herein the leaving group X, introduced as describedabove, has been substituted with an azido group in step 1), theresulting azido derivative has been subjected to catalitic reduction instep m), optionally followed by the hydrolis of Y performed in step n).

[0055] In a preferred form, and by way of an example, commercial chiralaspartic acid 1 is protected to yield derivative 2. Protective groups (Yin the scheme) are well known and require no particular description. Asan example, we may cite the tosyl group, which, in the reactionenvisaged in the invention, is described in Helv. Chim. Acta 1996, 79,1203-1216, or the benzyloxycarbonyl group, which, in the reactionenvisaged in the invention, is described in J. Am. Chem. Soc. 1986, 108,4943-4952. Thus, derivative 2 is cyclised to anhydride 3, as described,for example, in Helv. Chim. Acta 1994, 77, 2142-2146, and subsequentlyreduced to lactone 4 (see Helv. Chim. Acta 1994, 77, 2142-2146).

[0056] Compound 4 can be transformed into compound 5a by treatment withan alcohol ROH, where R is a straight or branched 1 to 14 term alkyl, oran arylalkyl, e.g. methanol, isobutanol or benzyl alcohol, in thepresence of a suitable transesterification catalyst, such as, forexample, an acid or a base (also in the form of resin), preferablyamine, such as trimethylamine. By treatment with a reactant suitable fortransforming the hydroxyl into an end group, e.g. alkyl or arylsulphonylchlorides, such as methane sulphonyl chloride in pyridine, triflicanhydride, 5a yields 5b, which by reaction with trimethylamine ortrimethyl phosphine yields 6a or 6b. Aminocarnitine or phosphoniumaminocarnitine can be obtained respectively from 6a and 6b byhydrolysing the ester and deprotecting the amino group according tocustomary procedures.

[0057] In accordance with the second embodiment of the process accordingto the invention, step c′) involves the opening of the lactone withiodotrimethylsilane, described in the literature when ethanol is used asthe alcohol (Helv. Chim. Acta, 79, 1996, 1203-1216) and makes itpossible to obtain the iododerivative 5b (X=iodine) with good yields.Similar lactone opening reactions can, of course, be easily envisagedwith other leaving groups.

[0058] Thus, intermediate 5b is treated in a nucleophilic substitutionreaction with trimethylamine or trimethylphosphine to yieldintermediates 6a or 6b, which, by alkaline hydrolysis and subsequentdeprotection of the amine group supply the desired products, e.g. ondeprotecting with 48% HBr, dibromohydrate is obtained. After a step onIRA 402 resin (OH⁻) aminocarnitine inner salt 8a or phosphoniumaminocarnitine inner salt 8b are obtained.

[0059] According to the third embodiment of the invention describedherein, on proceeding directly to the acid hydrolysis of 6a or 6b togive 8a or 8b the overall yield rises to 38% or 36% respectively in sixsteps. The enantiomeric purity of the aminocarnitine and of phosphoniumaminocarnitine thus obtained (determined by means of conversion to thederivative obtained with o-phthalaldehyde and L-acetylcysteine and HPLCanalysis, see J. Chromatography, 1987, 387, 255-265) was >99%.

[0060] In accordande with the fourth embodiment of the process accordingto the invention, step 1) provides the nucleophilic substitutionreaction of compund 5b with azido group to obtain compound 9. Thus theazido group of 9 was reduced to amino group in acidic condition in orderto protect the amino group formed during reduction reaction and tohydrolize the ester group to carboxylic acid. Subsequent step n)supplies the product 11, e.g. by the deprotection with 48% HBr, thedibromohydrate is obtained. After elution on IRA 402 resin (Cl⁻)3,4-diamino butyric acid dichlorohydrate was obtained in a overall yieldof 12.3% in six steps starting from 1.

[0061] The invention described herein also relates to the directproduction of chiral aminocarnitine, phosphonium aminocarnitine and 3,4diaminobutanoic acid derivatives, that is to say with the advantage ofallowing these compounds (of general formula corresponding tointermediate 7a, 7b or 10) to be obtained without first synthesisingaminocamitine or phosphonium aminocarnitine and 3,4 diaminobutanoic acidand then derivatising it, as, in contrast, is envisaged in theabove-cited patent applications MI98A001075 and PCT/IT99/00126 forcompounds 7a and 7b.

[0062] In fact, with the insertion of step a) of the appropriate Ygroup, after hydrolysis (or catalytic hydrogenation, in the case of anester removable with that technique) of intermediates 6a or 6b, thedesired derivatives of formula 7a or 7b is obtained. Compounds offormula 10 can be obtain by catalytic hydrogenation and hydrolysis ofintermediate 9.

[0063] Group X can be a leaving group selected, for example, from Br, I,Cl, OX′, where X′ can be alkyl or aryl sulphonyl (in particular mesyl ortosyl);

[0064] The following examples further illustrate the invention. Forreference purposes the reader is referred to the reaction scheme on page9.

EXAMPLE 1

[0065] The preparation of (R)-N-tosyl aspartic acid 2 (step a),(R)-N-tosyl aspartic anhydride 3 (step b), and(R)-3-(tosylamino)butano-4-lactone 4 (step c) was done as described inHelv. Chim. Acta 1996, 79, 1203-1216 (for 2) and in Helv. Chim. Acta1994, 77, 2142-2146 (for 3 and 4)

[0066] Preparation of the Isobutylester of(R)-4-iodo-3-(tosylamino)-butanoic acid 5b (Step c′)

[0067] The solution consisting of 4.1 g (16.06 mmol) of lactone 4.47 mlof anhydrous CH₂Cl₂ and 7.4 ml (80.3 mmol) of isobutyl alcohol wascooled to 0° C. in an ice bath and added with 6.55 ml (48.18 mmol) ofiodotrimethylsilane. The reaction was left overnight under magneticstirring at ambient temperature. After this time period water was addedand the mixture was left to stir for another 5 minutes at ambienttemperature. The organic phase was then washed with Na₂S₂O₃ 5%, H₂O,dried on Na₂SO₄, filtered and evaporated to dryness. The residue thusobtained was purified on a silca gel column, eluting with hexane/ethylacetate 75:25. 3.07 g of product were obtained as a waxy solid with ayield of 45%;

[0068]¹H NMR (CDCl₃): δ7.75 (d, 2H), 7.30, (d, 2H), 5.25 (d, 1H) 3.90(m, 2H), 3.55 (m, 1H), 3.30 (m, 2H), 2.70(dd, 1H), 2.50 (dd, 1H), 2.40(s, 3H), 1.90 (m, 1H), 1.58 (s, 2H), 0.90 (d, 6H);

[0069] ESI Mass=457 [(M+NH₄)⁺];

[0070] Elemental analysis for C₁₅H₂₂NO₄SI:

[0071] Calculated C, 41.01; H, 5.04; N, 3.18;

[0072] Found C, 42.15; H, 5.06; N, 3.02.

[0073] (As an alternative to chromatography, the crude product wascrystallised by ethyl ether/n-hexane to give the product with a yield of70%).

[0074] Preparation of the Isobutylester of (R)-N-tosyl-aminocarnitineiodide 6a (Step f)

[0075] 1.53 g of iodoester 5b (3.48 mmol) were solubilised in 16 ml ofanhydrous chloroform and added with 1.25 ml of 32.7% (6.96 mmol)trimethylamine in iBuOH. The reaction mixture thus obtained was left toreact at ambient temperature for 5 days. After this time period themixture was evaporated to dryness and the white residue was washed bydecanting with ethyl ether three times. 1.47 g of product were obtainedwith a yield of 85%;

[0076] MP=173-175° C.;

[0077] [α]²⁰ _(D)=+13.2 (c=0.49 in MeOH);

[0078]¹H NMR (CD₃OD): δ7.80 (d, 2H), 7.42 (d, 2H), 4.30 (m, 1H), 3.80(m, 2H), 3.50 (m, 2H), 3.30 (s, 9H), 2.45 (s, 3H), 2.35 (dd, 1H), 2.00(dd, 1H), 1.80 (m, 1H), 0.90 (d, 6H);

[0079] ESI Mass=371 [(M)⁺];

[0080] Ultimate analysis for C₁₈H₃₁N₂O₄SI:

[0081] Calculated C, 43.37; H, 6.27; N, 5.62;

[0082] Found C, 42.89; H, 6.47; N, 5.28,

[0083] Alternatively, the reaction was carried out in anhydrousdiethylformamide at ambient temperature for 18 hours, precipitating thereaction product with ethyl ether.

[0084] Preparation of (R)-N-tosyl-aminocarnitine inner salt 7a (Step g)

[0085] 3.5 g of 6a (7.022 mmol) were solubilised in 28 ml of NaOH 1N (28mmol) and left overnight to react under magnetic stirring at roomtemperature. After this period of time, the solution was evaporated todryness and the 4.8 g residue obtained was purified on a silica gelcolumn, eluting 8.2 with CHCl₃CH₃OH. 1.58 g of product were obtainedwith a yield of 71%;

[0086] MP=205-206° C. (dec.);

[0087] [α]²⁰ _(D)=+40.5 (c=0.4 in H₂O);

[0088]¹H NMR (CD₃OD): δ7.80 (d, 2H), 7.40 (d, 2H), 4.18 (m, 1H), 3.40(m, 2H), 3.30 (s, 9H), 2.40 (s, 3H), 1.90 (dd, 1H), 1.75 (dd, 1H);

[0089] Mass ESI=315 [(M+H)⁺];

[0090] KF=5.8%;

[0091] Elemental analysis for C₁₄H₂₂N₂O₄S:

[0092] Calculated C, 53.48; H, 7.05; N, 8.91;

[0093] Calculated with KF: C, 50.39; H, 7.29; N, 8.39;

[0094] Found C, 49.39; H, 7.17; N, 8.15,

[0095] Preparation of (R)-aminocarnitine inner salt 8a (Starting from7a, Step h)

[0096] To the mixture consisting of 530 mg of 7a (1.66 mmol) and 468 mg(4.98 mmol) of phenol were added 6 ml of 48% HBr. The solution obtainedwas then put in an oil bath preheated to 130° C. and left to reflux for18 hours. After this time period, the mixture was cooled, diluted withwater and extracted twice with ethyl acetate. The aqueous phase was thendried and the oily residue was extracted twice with acetonitrile andevaporated to dryness, until an insoluble solid in acetonitrile wasobtained. The solid residue was filtered and dried. 509 mg of(R)-aminocarnitine dibromohydrate were obtained with a yield of 95% (¹HNMR (D₂O): δ4.34 (m, 1H), 3.84 (m, 2H), 3.24 (s, 9H), 3.05 (m, 2H)).

[0097] After dissolving in 5 ml of water and elution on IRA 402 (OH⁻, 9ml) ion-exchange resin, 252 mg of product were obtained as inner salt(quantitative yield for this latter step); e.e>99% (determined byconversion to the derivative obtained with o-phthalaldehyde andL-acetylcysteine and HPLC analysis, see J. Chromatography, 1987, 387,255-265);

[0098] MP=150° C. (decomp);

[0099] [α]²⁰ _(D)=−21.13 (c=0.4 in H₂O);

[0100]¹H NMR (D₂O): δ3.64 (m, 1H), 3.40 (ddd, 2H), 3.22 (s, 9H), 2.40(ddd, 2H);

[0101] Mass (FAB)=161 [(M+H)⁺];

[0102] Ultimate analysis for C₇H₁₆N₂O₂:

[0103] calculated C, 52.47; H, 10.06; N, 17.48;

[0104] KF=7%;

[0105] Calculated with KF: C, 48.79; H, 10.14; N, 16.26;

[0106] Found C, 48.77; H, 11.34; N, 16.33.

EXAMPLE 2

[0107] Preparation of (R)-aminocarnitine inner salt 8a (Starting from6a, (Step i))

[0108] To the mixture consisting of 827 mg of 6a (prepared according toexample 1), (1.66 mmol) and 468 mg (4.98 mmol) of phenol were added 6 mlof HBr 48%. The solution obtained was then placed in an oil bathpreheated to 130° C. and left to reflux for 18 hours. Processing andpurification were then done as described in the recipe starting frominner salt 7a. The yield was 95%, and the analytical data coincided withthose reported above.

EXAMPLE 3

[0109] Preparation of (R)-aminocarnitine inner salt 8a (Starting from 1,without Purification of Intermediate Products 5b and 6a)

[0110] Compound 4, obtained as reported in the references cited above,was reacted with isobutyl alcohol and iodotrimethylsilane, as describedin the preparation of 5b. After washing with Na₂S₂O₃ 5% and H₂O, theorganic phase was dried on Na₂SO₄, filtered and evaporated to dryness.The residue thus obtained was reacted with trimethylamine as describedfor obtaining compound 6a, and after evaporation to dryness of themixture, the residue was hydrolysed as such with HBr, as alreadydescribed for obtaining compound 8a from 6a. The yield was 38% startingfrom 1, and the analytical data coincided with those reported above.

EXAMPLE 4

[0111] Preparation of the methylester of(R)-4-hydroxy-3-(benzyloxycarbonylamino) butanoic acid 5a (Step d)

[0112] Compound 4 (2.35 g, 10 mmol) (Y=benzyloxycarbonyl, prepared asdescribed in J. Am. Chem. Soc. 1986, 108, 4943-4952) was solubilised inMeOH (15 mL) and added with 18.8 mL (80 mmol) of 25% trimethylamine inMeOH by weight. The reaction was left to stir at room temperature forthree days, whereupon CHCl₃ was added and the organic phase was washedwith HCl 1N and then with NaCl s.s.. The organic phase was dried onNa₂SO₄, filtered and vacuum evaporated to dryness to yield 2.27 g of anoil containing 90% of product (as shown by NMR analysis) and 10% ofstarting product;

[0113]¹H NMR (CDCl₃): δ7.35 (s, 5H), 5.45 (br, 1H), 5.10 (s, 2H), 4.08(m, 1H), 3.75 (d, 2H), 3.65 (s, 3H), 2.65 (d, 2H), 1.60 (brs, 1H). Thisproduct was used as such in the following reaction.

[0114] Preparation of the methylester of(R)-4-mesyloxy-3-(benzyloxycarbonylamino) butanoic acid 5b (Step e)

[0115] To a solution of 5a (2 g, 7.5 mmol) in anhydrous pyridine (20mL), cooled to 0° C. in an ice bath, were added 0.87 mL (11.3 mmol) ofmethane sulphonyl chloride. The solution was then left to stir for onenight at room temperature. CHCl₃ was added and the organic phase waswashed with HCl 1N and then with NaCl s.s.. The organic phase was driedon anhydrous Na₂SO₄, filtered and vacuum evaporated to dryness to yield1.96 g of a solid containing approximately 70% product. (¹H NMR (CDCl₃):δ7.35 (s, 5H), 5.45 (br, 1H), 5.20 (s, 2H), 4.33 (brm, 3H), 3.70 (s,3H), 3.00 (s, 3H), 2.70 (d, 2H)). This product was used as such in thefollowing reaction.

[0116] Preparation of the methylester of(R)-N-benzyloxycarbonyl-aminocarnitine methane sulphonate 6a (Step f)

[0117] To a solution of 5b (527 mg, 1.52 mmol) in 5 mL of anhydrousCHCl₃ were added 0.72 mL of a 25% solution by weight of trimethylaminein MeOH, and the solution was left to stir for 5 days at roomtemperature. A solid containing approximately 65% product was obtainedby vacuum evaporation of the solvent (¹H NMR (CD₃OD): δ7.32 (brs, 5H),5.10 (s, 2H), 4.50 (m 1H), 3.65 (s, 3H), 3.50 (m, 2H), 3.20 (s, 9H),2.70 (s, 3H), 2.65 (d, 2H).

[0118] Preparation of (R)-aminocarnitine inner salt 8a Starting from theMethylester of (R)-N-benzyloxycarbonyl-aminocarnitine methane sulphonate6a (Steps g and h)

[0119] The preparation is done by hydrolysing the ester and deprotectingthe amine group by means of catalytic hydrogenation according to routineprocedures.

EXAMPLE 5

[0120] Preparation of (R)-N-decanesulphonyl-aminocarnitine inner salt 7a(Steps a-g)

[0121] The compound is prepared as described when Y is equal to tosyl,using decansulphonyl chloride instead of tosyl chloride in step a) ofthe process and then operating as described in the foregoing examples.

EXAMPLE 6

[0122] Preparation of (R)-3-tosylamino-4-(trimethylphosphonium)-butanoicacid isobutylester iodide (6b) (Step f).

[0123] To 2 g of 5b, (4.5 mmol) 5.4 ml of trimethylphosphine (1Msolution in THF) were added. The resulting solution was stirred at roomtemperature for 5 days, then the solvent was removed under vacuum andthe residue was triturated three times with diethilic ether to give 1.81g of 6b (78%);

[0124] MP=159-161° C. (decomp);

[0125] [α]_(D) ²⁰=+21 (c=0.51 in MeOH);

[0126]¹H NMR (CD₃OD): δ7.75 (d, 2H), 7.40 (d, 2H), 4.10 (m, 1H), 3.70(d, 2H), 2.60 (m, 2H), 2.40 (s, 3H), 2.30 (m, 1H), 2.10 (m, 1H), 2.00(d, 9H), 1.80 (m, 1H), 0.82 (d, 6H);

[0127] Elemental analysis for C₁₈H₃₁NO₄PSI:

[0128] Calculated C, 41.95; H, 6.06; N, 2.71; S, 6.22;

[0129] Found C, 42.33; H, 6.16; N, 2.88; S, 6.22.

[0130] Preparation of(R)-3-tosylamino-4-(trimethylphosphonium)-butanoate (7b) (Step g).

[0131] 1.71 g of 6b (3.3 mmol) were solved in 15.5 ml of NaOH 1N andstirred at room temperature for 20 h, then the aqueous phase wasevaporated under vacuum and the crude product was purified by flashchromatography using as eluent a gradient of CHCl₃/CH₃OH starting from9/1 to 5/5, to give 530 mg of 7b in 41.4% yield;

[0132] MP=192-194° C. (decomp);

[0133] [α]_(D) ²⁰=+45 (c=0.5 in MeOH);

[0134]¹H NMR (D₂O) δ7.66 (d, 2H), 7.35 (d, 2H), 3.86 (m, 1H), 2.26-2.50(m, 5H), 1.72-1.92 (m, 11H);

[0135] KF=6.1%;

[0136] Elemental analysis for C₁₄H₂₂NO₄PS:

[0137] Calculated C, 50.74; H, 6.69; N, 4.22, S 9.67;

[0138] Calculated with KF: C, 47.66; H, 6.96; N, 3.97; S, 9.08;

[0139] Found: C, 47.50; H, 6.85; N, 3.92; S, 8.78.

[0140] Preparation of (R)-3-amino-4-(trimethylphosphonium)-butanoate(8b) (Step i).

[0141] A round bottom flask containing a mixture of 1.9 g of 6b (3.7mmol), 1.04 g of phenol (11.06 mmol) and 27 ml of HBr 48% was placed inan oil bath previously heated at 130° C. and refluxed for 18 hours. Thereaction mixture was then allowed to reach the room temperature, dilutedwith water and extracted twice with AcOEt. The aqueous layer wasevaporated under vacuum, the residue was taken up several times withCH₃CN (evaporating under vacuum every time) until a solid residue,insoluble in CH₃CN, was obtained. The solid was filtered and thendissolved in 5 mL of water and eluted over an exchange ion resin IRA 402(OH⁻) 50 ml. After evaporation under vacuum, the residue was taken uptwice with CH₃CN and then several times with CH₃OH (every timeevaporating the solvent under vacuum) to give 600 mg of 8b with a yieldof 92%; e.e>99% (determinated as described in ref. 9);

[0142] MP=66-68° C. (decomp);

[0143] [α]_(D) ²⁰=−21.3° (c=1 in H₂O);

[0144]¹H NMR (D₂O) δ3.30 (m, 1H), 2.10-2.35 (m, 4H), 1.75 (d, 9H);

[0145] KF=16.3%;

[0146] Elemental analysis for C₇H₁₆NO₂P:

[0147] Calculated C, 47.45; H, 9.10; N, 7.90;

[0148] Calculated with KF: C, 39.71; H, 9.44; N, 6.61;

[0149] Found: C, 40.30; H, 9.49; N, 6.79.

EXAMPLE 7

[0150] Preparation of (R)-3-tosylamino-4-azidobutanoic acidisobutylester (9).

[0151] To a solution of 1 g of 5b (2.27 mmol) in 10 ml of CH₃CN and 2 mlof water, NaN₃ (0.592 g, 9.11 mmol) was added. The resulting suspensionwas stirred at 80° C. for 6 hours, then the solvent was removed undervacuum and the crude residue was diluted with water and extracted twicewith ether. The organic layer was dried over anhydrous Na₂SO₄, andfinally evaporated to obtain 0.790 g of crude product as a light yellowwax which was used without further purification with a yield of 98%;

[0152] [α]_(D) ²⁰=+15.2° (c=0.45 in MeOH);

[0153]¹H NMR (CDCl₃): δ7.76 (d, 2H), 7.30 (d, 2H), 5.30 (d, 1H), 3.80(m, 2H), 3.70 (m, 1H), 3.40 (m, 2H), 2.50 (m, 2H), 2.40 (s, 3H), 1.86(m, 1H), 0.90 (d, 6H);

[0154] Elemental analysis for C₁₅H₂₂N₄O₄S:

[0155] Calculated C, 50.83; H, 6.25; N, 15.80; S 9.04;

[0156] Found C, 51.15; H, 6.34; N, 15.41; S, 8.71.

[0157] Preparation of (R)-3-tosylamino-4-aminobutyric acid hydrochloride(10).

[0158] A solution of 1.1 g of 9 (3.0 mmol) in 143 ml of HCl 2N washydrogenated in H₂ atmosphere overnight at 60 psi. After this time theresidue was filtered and the acqueous phase was left under magneticstirring for additional 48 hours at 40° C. Then the water was evaporatedunder vacuum and the residue was taken up twice with CH₃CN (evaporatingunder vacuum every time) until a solid residue, insoluble in CH₃CN, wasobtained. The pale yellow wax was filtered and dried to give 0.300 g offinal product with a yield of 32% which was used without furtherpurification;

[0159] [α]_(D) ²⁰=+43° (c=0.25 in H₂O);

[0160]¹H NMR (D₂O): δ7.70 (d, 2H), 7.35 (d, 2H), 3.75 (m, 1H), 3.00 (m,2H), 2.10-2.40 (m, 5H).

[0161] Preparation of (R)-3,4-diaminobutanoic acid dihydrochloride (11)

[0162] A round bottom flask containing a mixture of 0.600 g of 10 (1.94mmol), 547 mg of phenol (5.82 mmol) and 7.5 ml of HBr 48% was placed inan oil bath previously heated at 130° C. and refluxed for 18 hours. Thereaction mixture was then allowed to reach the room temperature, dilutedwith water and extracted twice with AcOEt. The aqueous layer wasevaporated under vacuum, the residue was taken up several times withCH₃CN (evaporating under vacuum every time) until a solid residue,insoluble in CH₃CN, was obtained. The solid was filtered and dried togive 0.23 g of (R)-3,4-diaminobutanoic acid as dihydrobromide salt (95%)which was solved in 5 ml of water. After elution over 75 ml of exchangeion resin IRA 402 (Cl⁻) and evaporation under vacuum, the residue wastaken up twice with CH₃CN and then several times with CH₃OH (every timeevaporating the solvent under vacuum) to give 0.123 g of 11 as a whitewax with a yield of 78%;

[0163] [α]_(D) ²⁰=+4.3° (c=1% H₂O);

[0164]¹H NMR (D₂O, DDS): δ3.85 (m, 1H), 3.35 (m, 2H), 2.75 (dd, 1H),2.60 (dd, 1H);

[0165] KF=21.4%;

[0166] Elemental analysis for C₄H₂N₂O₂Cl₂:

[0167] Calculated C, 25.14; H, 6.33; N, 14.66; Cl, 37.11;

[0168] Calculated with KF: C, 19.76; H, 7.37; N, 11.52; Cl, 29.17;

[0169] Found: C, 19.49; H, 7.16; N, 11.37; Cl, 38.70.

1. Process for the preparation of compounds with the formula:

in which W is Q(CH₃)₃ where Q is N or P or W is NH₃ Y is hydrogen or oneof the following groups: —R₁, —COR₁, —CSR₁, —COOR₁, —CSOR₁, —CONHR₁,—CSNHR₁, —SOR₁, —SO₂R₁, —SONHR₁, —SO₂NHR₁, where R₁ is a straight orbranched, saturated or unsaturated alkyl containing from 1 to 20 carbonatoms, optionally substituted with an A₁ group, where A₁ is selectedfrom the group consisting of halogen, C₆-C₁₄ aryl or heteroaryl, aryloxyor heteroaryloxy, which can optionally be substituted with straight orbranched, saturated or unsaturated lower alkyl or alkoxy, containingfrom 1 to 20 carbon atoms, halogens; said process comprises thefollowing steps: a) conversion of D-aspartic or L-aspartic acid to N—Ysubstituted D-aspartic or L-aspartic acid; b) conversion of the N—Ysubstituted D-aspartic or L-aspartic acid to the respective anhydride;c) reduction of the anhydride obtained in step b) to the corresponding3-(NH—Y)-lactone; d) opening of the lactone obtained in step c) to yieldthe corresponding D- or L-3-(NH—Y)-amino-4-hydroxybutyric acid; e)transformation of the 4-hydroxy group of the D- orL-3-(NH—Y)-amino-4-hydroxybutyric acid into a leaving group; f)substitution of the leaving group in position 4 of the D- orL-3-(NH—Y)-aminobutyric acid with a trimethylammonium group, ortrimethylphosphonium group; g) hydrolysis of the ester group; and, if sodesired, h) restoration of the amino group; i) one pot hydrolysis of theester and protective group on N group at position 3; l) substitution ofthe leaving group in position 4 of the D- or L-3-(NH—Y)-aminobutanoicacid with an azido group; m) reduction of the azido group to amino groupand concurrent hydrolysis of the ester group, and if so desired, n)restoration of the amino group.
 2. Process according to claim 1, inwhich step c is directly followed by step c′) consisting in the openingof the lactone to yield the corresponding D- orL-4-X-3-(N—Y)-aminobutyric acid, where X is a leaving group and Y is asdefined above, and in which step c′) is followed steps f)-h) as inclaim
 1. 3. Process according to claim 1, in which step f) is followedby step i) consisting in hydrolysis of the ester and deprotection of the3-amino group to yield R or S aminocamitine or phosphoniumaminocarnitine directly.
 4. Process according to claim 1, in which groupY is tosyl.
 5. Process according to claim 1 in which steps l)-n) allowthe preparation of a chiral synthon such as R or S 3,4 diaminobutyricacid.
 6. Process according to claim 1 in which the leaving group isiodine.
 7. Process according to claim 1, in which said process isconducted without purification of the intermediate products.
 8. Compound8b as potential CPT inhibitor with antiketotic and antidiabetic activityand as useful intermediate for the synthesis of pharmaceutically activecompounds.